antidepressants in oncology

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Antidepressants in Oncology: Reason and Choice

Riccardo GV Torta, MD; Marco Miniotti, PsycholD, and Paolo Leombruni, MD

Corresponding author: Prof. Riccardo GV Torta Department of Neuroscience, University of Turin Clinical and Oncological Psychology Unit, Via Cherasco 15, 10126, Turin, Italy Telephone: 0039-011-6636327 Fax: 0039-011-6963487 Email: riccardo.torta@unito.it

Acknowledgments None. Funding No funding was received for this article. Declaration of interest The authors report no declarations of interest. Other disclosures None. 1

Summary The medications known as antidepressants are the group of psychotropic drugs used most often in psycho-oncology for their wide spectrum of action, ranging from mood improvement to the control of anxiety and pain. Antidepressants are drugs that act on the whole body rather than just the central nervous system. They also modulate the hormonal and immune systems, particularly normalizing stress-induced alterations. In oncology, the choice of an antidepressant must involve consideration of the symptoms and the dimensional aspects more than strict diagnostic criteria. A careful evaluation of the balance between effectiveness and safety, considering the possibility of interactions between antidepressants and oncological treatments, is crucial. In that context, this paper discusses each class of antidepressant relative to the present research literature concerning the specific use of each drug in oncological patients, noting that criteria of effectiveness and safety can differ from those established for the general psychiatric population without organic comorbidity. Finally, some aspects of the use of antidepressants in the treatment of patients with pain will be discussed, as these drugs exert an intrinsic antalgic activity even when depressed mood is not present. Indeed, antidepressants act not only on the somatic modulation of pain, but they are also effective on the emotional and cognitive aspects of pain, therefore intensifying the analgesic activity of traditional painkillers.

Key words Antidepressants, Oncology, Pain.

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Introduction Despite evidence that the treatment of depression induces a significant improvement of the patients quality of life and reduces mortality from cancer, pharmacological treatment is used in less than 5% of depressed oncological patients (1-4). Furthermore, the use of antidepressants is no longer limited to the treatment of mood disorders but has been expanded to include treatment of anxiety disorders, pain and the somatic consequences of chronic stress (5).

Within psycho-oncology, it is important to reduce the use of several classes of drugs, such as benzodiazepines and neuroleptics, that mainly exert a symptomatic and tactical activity that is useful in critical situations and short term interventions, but their use is inadvisable as long term treatments because of their propensity to increase fatigue. More appropriate is the use of antidepressants (and sometime atypical antipsychotics) that exert a curative activity and, for newergeneration antidepressants, have a high safety in long-term treatments (6).

In fact, the first criteria that must be met when choosing a psychopharmacological compound in psycho-oncology relate to safety and tolerability, noting that these criteria can change among the different oncotypes. An antidepressant must primarily manage specific clusters of symptoms that are more frequent in depressed oncological patients, including pain, fatigue, hyporexia and weight loss; these symptoms are no less important than nuclear depressive symptoms such as anhedonia and mood deflection.

The next step in choosing a compound will be the evaluation of pharmaco-dynamic and kinetic characteristics of antidepressants, particularly when used concomitantly with oncological drugs. For example, the use of paroxetine with taxanes is to be avoided, and caution must be used to prevent specific side effects that can be devastating in some patients, such as the anticholinergic activity of tricyclic antidepressants (TCA) in patients with reduced gastrointestinal motility, the additive effect

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of serotonergic antidepressant-related nausea with similar chemotherapeutic side effects, or an antihistaminergic sedation in asthenic patients (7-9)

Iatrogenic factors inducing depression Several drugs used in general medicine and sometimes in oncological patients, such as betablockers, anti-hypertensive drugs, and barbiturates, can induce depression. In addition, the widespread use (for nausea or sedation) of high-potency neuroleptics, such as haloperidol, can cause dopaminergic depletion with consequent depression. Alternatively, corticosteroids can induce both depression and elation, depending on the individuals response.

Special attention must be paid to the use of interferon because of the possibility of its inducing a worsening of mood, related to the increase of pro-inflammatory cytokines (10-13).

Also of note, an iatrogenic estrogenic depletion (surgically or pharmacologically induced) can cause a severe depression and an increase of the hot flushes phenomenon. For the latter, an estrogenic implementation is obviously inconvenient, and several antidepressants have demonstrated good effectiveness, with a normalization of thermoregulation due to estrogenic production within the central nervous system induced by antidepressants (14-15).

It is very important to be aware that the neurotoxicity caused by several chemotherapeutic agents (e.g., taxans, vinca alkaloids, or heavy metals) can induce not only peripheral neuropathies but also cognitive and emotional problems, such as depressed mood, memory impairment, and irritability (16-20).

Reasons for an antidepressant intervention in oncological patients Depression in oncological patients causes a worsening of quality of life, a higher risk for the emotional and somatic consequences of chronic stress, physical, social and occupational functional impairment, a reduced adherence to diagnostic procedures and treatments as well as a dramatic 4

increase in suicide risk. In spite of the high prevalence of depression in oncological patients (with wide variability depending on the disease phase and treatment), only a small percentage of depressed oncological patients take advantage of antidepressant treatment (4, 21-24). The poor management of depression increases pain perception and reduces the patients tolerance for the side effects of oncological therapies.

It is mandatory to make a correct diagnosis of any form of depressed mood in a patient with cancer. Recommendations include using self-evaluation instruments and then studying in depth, with a semistructured clinical interview, those patients that demonstrate scores higher than a screening cutoff (25).

A serious clinical mistake is to consider depression in oncological patients as an unavoidable pathology and consequently not responsive to drugs. The correct antidepressant treatment can improve depression in oncological patients similarly to functional depressed patients (26). However, an antidepressants effectiveness in oncology must be evaluated not based on a simple rating scale score reduction but, above all, based on functional recovery, improvement in the quality of life and the change toward more adaptive coping styles.

The pathogenesis of emotional disorders in oncology is strictly related to the biopsychosocial model, with differing importance among individuals and disease phases of the biological, emotional-cognitive and social components. Consequently, the most efficacious therapeutic interventions will be an integration of a pharmacological intervention to correct the biologic alterations (e.g., transmitter-related, hormonal, immunological, and neurotrophic) and/or a tailored psychotherapy to modify the patients cognitive and emotional defense strategies and/or supporting the patient when the social context problematically affects emotional parameters.

In this context, antidepressants are the most efficacious class of medication because of their activity on mood, anxiety, stress, and pain (27,28). 5

Guideline for the use of antidepressants in oncological patients When the diagnosis of depression is made, antidepressants must be used as the pharmacological first line of treatment. In fact, the use of benzodiazepines when depressive symptoms are present is still frequent. Oncologists should have a basic knowledge of antidepressants to prescribe as a first step for patients that refuse a psychiatric consultation, thus avoiding the consequences of lack of treatment and maintaining direct management of the patient. The most favorable conditions are the presence of a medical psycho-oncologist on the oncological team or the presence of a dedicated psychiatrist, expert in the use of antidepressants in oncological patients.

In oncology, the greatest risk of non-adherence is present in the first weeks of an antidepressant treatment, when side effects outweigh the therapeutic response. This is because the latency of antidepressant activity on anxiety and mood is about three to four weeks. During this latency period, it is essential to provide the patient with adequate information, psychosocial support (from the therapeutic staff and family) and, when necessary, pharmacological management of the antidepressants side effects (such as activation, nausea, or dizziness).

In almost all patients with severe depression, suicidal ideation can be present. An increased risk of suicide is likely in those patients in which a psychomotor disinhibition, induced by an antidepressant, takes place before a nuclear improvement of depression is reached. In this situation, for an outpatient, monitoring of the patient by the family is mandatory, and it is important to have an